EGFRvIII is one of several EGFR variants that are caused by gene rearrangement accompanied by EGFR gene amplification. EGFRvIII consists of a 267 amino acid in-frame deletion in the extracellular domain of EGFR. EGFRvIII is the most commonly occurring variant of the epidermal growth factor (EGF) receptor in human cancers. During the process of gene amplification, a 267 amino acid deletion occurs in the extracellular domain creating a novel junction which can serve as tumor specific neo epitope for monoclonal antibodies. This variant of the EGF receptor contributes to tumor progression through constitutive signaling in a ligand independent manner. EGFRvIII is not known to be expressed on any normal tissues. The excellent tumor selectivity of EGFRvIII expression establishes EGFRvIII as an ideal antigen for targeting with a BiTE antibody construct. Contribution of EGFRvIII to tumor progression suggests a dependence of cancer cells on expression of EGFRvIII and therefore further supports its suitability as a target.
It has been shown that EGFRvIII is frequently expressed in two types of malignant central nervous system tumors, namely Glioblastoma Multiforme and Anaplastic Astrocytoma. For both diseases there exists a significant unmet medical need. This is exemplified by the poor overall survival under standard of care with 13.6% at 2 years for Glioblastoma Multiforme and 25.9% at 5 years for Anaplastic Astrocytoma. Currently the standard of care for Glioblastoma Multiforme consists of surgical resection of the tumor, which is most often hindered by the diffuse growth pattern of the tumor and the requirement to preserve functionally essential regions of the brain. Surgery is followed by adjuvant irradiation and chemotherapy. For Glioblastoma Multiforme and Anaplastic Astrocytoma treated according to the current standard of care recurrence is the norm, with eventually fatal outcome in virtually all patients.
EGFRvIII expression in Glioblastoma Multiforme and Anaplastic Astrocytoma constitutively activates the PI3 kinase signaling pathway and is associated with worsened prognosis in Glioblastoma Multiforme and Anaplastic Astrocytoma. Also it has been described that EGFRvIII is coexpressed with CD133 and defines a population of cancer stem cells in Glioblastoma Multiforme (Emlet et al., Cancer Res, 2014, 74(4):1238-49). Furthermore it has been demonstrated that by the mechanism of an intercellular antigen transfer EGFRvIII can be transferred to the cell surface of antigen negative tumor cells. By this mechanism expression heterogeneity of EGFRvIII, which has been shown for some cases of Glioblastoma Multiforme, might be overcome as an obstacle for treatment efficacy, especially in the case of using an EGFRvIII specific BiTE antibody construct, which provides a highly effective cytotoxic mode of action compensating for potentially low levels of target antigen achieved by intercellular antigen transfer.
EGFRvIII expression has also been described in several other tumor entities (Wikstrand, C J. et al., Cancer Research 55(14): 3140-3148 (1995); Ge H. et al., Int J Cancer. 98(3):357-61 (2002); Moscatello, G. et al., Cancer Res. 55(23):5536-9 (1995); Garcia de Palazzo, I E. et al., Cancer Res. 53(14):3217-20 (1993); Olapade-Olaopa, E O. et al., Br J Cancer. 82(1): 186-94 (2000)). Therefore, given the exquisite tumor selectivity of EGFRvIII, treatment with an EGFRvIII specific BiTE antibody construct might also be beneficial in other, select cancer types or subtypes. Potentially selection of cancer types, subtypes or patients for treatment could be guided by various methods testing for expression of EGFRvIII in the tumor.
As there is still a need for having available further options for the treatment of solid tumor diseases related to the overexpression of EGFRVIII, such as glioblastoma, astrocytoma, medulloblastomas, breast carcinomas, non-small cell lung carcinomas, ovarian carcinomas, prostate carcinomas, central nervous system, there are provided herewith means and methods for the solution of this problem in the form of a bispecific antibody construct having a binding domain directed to EGFRVIII on the surface of tumor target cells and a second binding domain directed to CD3 on the surface of T cells.